Pathobiology of Blast Injury A.M. Dennis and P.M. Kochanek

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A.M. Dennis and P.M. Kochanek

Introduction

Injury due to explosive detonation has previously been isolated to industrial accidents and soldiers and civilians in areas of armed military action. Substantial data regarding blast-related patterns of injury has come from military reports and research, and there have been significant advances in protective vehicle and body armor, ‘far forward’ provision of medical care, and evacuation procedures. Despite this, explosive munitions and improvised explosive devices still comprise the majority of combat morbidity and mortality [1 – 4]. There is also increased targeting of civilians in a global political environment where incendiary devices are a principle instrument of modern terrorism [5 – 7]. Events in preceding decades indicate a critical need for both civilian and military emergency and intensive care providers to understand the pathophysiology and management of blast-related injuries.

Reviews of military casualties and terror-related bombings reveal that while pulmonary and orthopedic consequences of blast injury are predominant, traumatic brain injury (TBI) is more prevalent than initially thought. Data from Israel and Ire- land demonstrate a striking “excess number of head and brain injuries” when anatomic analyses are performed [6, 7]. There is emerging evidence that blast-related TBI may be a unique entity, produced by kinetics specific to explosive force, and exacerbated by a milieu of extra-cerebral consequences.

In this chapter, we will 1) discuss the general pathomechanisms of blast injury, 2) review the current information on this unique mechanism that manifests specifically in blast-related neurotrauma, 3) discuss experimental studies of the cellular and molecular response to blast-induced neuronal and axonal damage, 4) review the concept of secondary injury in blast-induced TBI, and 5) discuss further directives in therapy for this unique brain injury medium.

Blast Injury: Pathomechanics

Blast overpressure occurs as heated and compressed air molecules expand outward from the detonation epicenter. The leading edge of this blast wave forces an instanta- neous and extreme rise in surrounding air pressure (positive phase), followed by collapse to a sub-atmospheric level (negative phase) before normalizing. Figure 1 depicts this stereotypic pressure rise and fall, known as a Friedlander wave. Primary blast injuries result from the cussive effect of the leading blast overpressure energy wave as it impacts the body. In open spaces, a single wave is produced, but in closed environments, the energy is deflected off various surfaces, impacting victims repeat-

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Figure 1. Idealized Friedlander Wave, depicting rise in ambient atmospheric pressure and subsequent fall to subatmospheric levels before equilibration.

edly, and with magnified intensity. Spalling describes the forceful movement of ener- gized fluid into less dense tissues, and differential tissue inertia results in non-uni- form acceleration and shearing at interfacing planes. Projectile debris from the device or immediate surroundings inflict blunt or penetrating trauma, referred to as secondary blast injury. This is of particular concern with improvised explosive devices or ‘dirty bombs’, frequently laden with objects such as nails, glass, or ball bearings in order to maximize destruction. The magnitude of the blast can displace the victim’s entire person, resulting in tertiary or displacement injury from collision with stationary objects. Consequences of the detonation such as building collapse contribute to quaternary injury, and a quinary mechanism occurs with exposure to or inhalation of toxic, infectious or radioactive substances [8 – 15].

Primary injury from blast overpressure predictably involves hollow organs such as the ears, respiratory tract, and abdominal viscera. Hearing loss is extremely common, and in an organ evolved to magnify subtle sound waves, rupture of the tym- panic membrane is pathognomonic for significant blast overpressure exposure. The majority of blast-related literature addresses lung pathology (blast lung): Alveolar rupture, pneumothorax, pulmonary contusion, and hemorrhage. Respiratory failure may result, while arterial air emboli from pulmonary disruption sometimes circulate to the cerebral vasculature or coronary arteries with deleterious effects. In the abdominal compartment, rapid gaseous distension and violent compaction of viscera results in rupture or hemorrhage, and can occur without outward signs. In fact, life-threatening internal injuries due to blast overpressure are notable for lack of external evidence of trauma.

Subsequent to primary blast overpressure, secondary and tertiary mechanisms yield a spectrum of life-threatening injuries not unlike more familiar blunt and penetrating trauma incurred in motor vehicle crashes, falls, gunshots, and stabbings.

However, serious, simultaneous involvement of multiple anatomic regions is a hallmark of critical explosive injury. Bleeding from shrapnel wounds, traumatic ampu- tations, fractures, and internal injuries frequently leads to hemorrhagic shock and a systemic inflammatory response, while thermal blast energy and fire can cause extensive burns. All of this generally ensues amid mass casualty and chaos, sometimes in austere environments, and often in the context of limited or overwhelmed medical resources.

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Blast-related Neurotrauma: ‘Shell Shock’ Revisited

A retrospective study of terror-related ballistic injuries in Israel (firearm and explosive), found a 17 % mortality associated with internal injuries involving the thorax and abdomen, and 80 % mortality when similar patients also sustained a head injury [6]. TBI is the most common cause of death in terrorist bombings. Blast-related severe TBI victims, with or without concomitant extra-cerebral trauma, are an important population as the overwhelming majority go on to die despite survival to hospital admission. While previous explanations blamed air embolism for central nervous system (CNS) injury, blast TBI is a more complex entity involving multiple mechanisms and levels of injury. Acutely, victims demonstrate a spectrum of neurologic dysfunction, from transient loss of consciousness to coma. Long-term survi- vors frequently suffer chronic cognitive impairment or psychological manifestations.

The terms ‘shell shock’ and ‘commotio cerebri’ were coined decades ago to describe the occurrence of these neurologic phenomena without external evidence of trauma or obvious intracranial pathology [16 – 18].

Blunt force and penetrating trauma cause skull fractures and discreet mass lesions: Cerebral contusions, hemorrhages, and lacerations. In TBI, inertial and rota- tional forces also result in global damage with diffuse axonal injury (DAI) and cerebral edema. DAI is observed in acceleration-deceleration mechanisms such as motor vehicle crashes, frequently implicated in traumatic coma, and is distinguished by widespread axonal swelling and retraction balls in cerebral white matter, cerebellum, and brainstem [19]. Other hallmark features include microglial activation and punctate hemorrhages in these locations, as well as lesions in the corpus callosum. Evi- dence suggests that clinical and experimental blast TBI is strikingly similar to DAI, with abnormal axonal morphology, cerebral edema, punctate hemorrhages in white matter, choroid plexus, cerebellum and brainstem, and occasional subdural or subarachnoid bleed [20, 21]. Injuries resulting from incendiary devices are multifaceted in nature, and the secondary and tertiary mechanisms certainly account for a por- tion of observed TBI. However, blast TBI as a unique consequence of primary blast overpressure is currently being investigated as the etiology of diffuse brain injury in the absence of obvious external violence, and as a result of “kinetic energy transfer of blast overpressure to the CNS” [24]. This has serious implications in the critically wounded blast victim, as extra-cerebral injuries exacerbate head injury with secondary insults, and TBI can impair appropriate systemic physiologic compensation in hemorrhagic shock [22, 23].

While blast waves may travel directly through the cranial vault, alternately increasing and decreasing intracranial pressure (ICP) and shearing tissues, the relative homogeneity of the brain and its encapsulation in a hard, bony case make direct transcranial injury seem unlikely to explain all of the findings and possibly does not represent the primary mechanism of injury. Soldiers wearing protective helmets still manifest varying degrees of intracranial blast injury [2]. Furthermore, Cernak et al.

found similar neuropathology in physically secured blast injured rats, regardless of whether the head was shielded from direct impact or not [24]. One explanation is that as blast overpressure oscillates through the torso, compression of organs and vessels forces blood into the cranium as a surge of arterial flow or increased venous backpressure. Blast waves can propagate in air and water, and blast overpressure may also travel cranially via a path of least resistance out of the thorax in blood vessels and spinal fluid [18]. Water is denser than air, and because a fluid blast overpressure wave is actually more intense, serial Friedlander waves transmitting into

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Figure 2. Plausible mechanism for diffuse brain injury due to blast energy. a Initial positive pressure phase of the Friedlander wave impacts the rigid skull, while the stationary brain lags behind. b The subsequent negative pressure phase causes a whip-lash motion back towards the energy source, while the brain has begun to move in the opposite direction, resulting in coup-contre-coup and DAI spectrums of brain injury.

the cranial vault could certainly generate the observed pattern of injury. Another possible mechanism is that the rapid positive pressure phase first encounters and accelerates the rigid skull. The brain is unattached, suspended in spinal fluid, and lags behind, suffering an initial blow on the blast-facing surface. When the subsequent lower energy negative wind pulls the head in the opposite direction, the brain is struck again, this time on the opposite, non-blast facing surface (Fig. 2). While additional investigation is needed to elucidate whether blast overpressure itself results in altered level of consciousness and unique brain pathology, or whether this is simply another mechanism of acceleration-deceleration injury, there is an emerging body of evidence that suggests that blast injury may produce a new pattern of brain injury in civilian bombings and modern urban warfare casualties. If a unique pathobiology of brain injury is produced by blast injury, a unique and tailored approach to both resuscitation and neurointensive care may be necessary to maximize outcomes.

Experimental Blast-Induced TBI: Implications of Cellular and Molecular Mechanisms of Neuronal and Axonal Injury

Studies in a number of experimental models of blast-induced injury have been car- ried out, and although many questions remain, evidence is provided supporting contributions of DAI, oxidative stress, cellular stress with immediate early gene activation, calcium accumulation, decreases in tissue magnesium, energy failure, neuronal death, and edema.

A number of clinical and experimental studies have observed evidence of DAI in blast TBI. Using a rodent non-penetrative blast model, Säljö et al. demonstrated failure of heavy chain phosphorylated neurofilament protein (p-NFH) migration out of the neuron perikarya into the axon where they are an integral component of cyto- skeletal integrity and axonal transport [25]. This response was found to be dose related, and more pronounced in the blast-exposed hemisphere, though both hemi- spheres were involved. Accumulation of p-NFH in the perikarya was present from 18 h to 7 days, and normal axonal distribution of p-NFH had returned at 21 days. Kaur et al have explored inflammation in experimental blast TBI and found a significant, widespread increase in activated microglia (assessed immunohistochemically) in the

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gray and white matter, as well as in the choroid plexus of ventricles [26, 27]. Addi- tionally, at 7 – 14 days after injury in cerebral and cerebellar cortices there was non- specific “darkening” of dendrites and axons associated with microglial cells, suggesting neuronal alterations as a consequence of blast.

Oxidative stress is a recognized secondary injury cascade in TBI, induced by the primary insult and also an important consequence of key secondary injury processes such as excitotoxicity, mitochondrial dysfunction/failure, nitric oxide (NO) synthesis, peroxidase activation, and inflammation. Reactive oxygen species (ROS) induce membrane lipid peroxidation, DNA damage, protein oxidation, and lipid and protein nitration, among other mechanisms. Oxidative damage can initiate necrotic, apoptotic, and autophagic cell death cascades. Endogenous antioxidants, including small molecules such as ascorbate, can mitigate the damage, however, there is strong evidence that these pathways are often overwhelmed – including studies in human TBI [28]. In rodents exposed to either whole body or local pulmonary blast, remark- ably, important biochemical consequences were noted in brain specifically the highly vulnerable hippocampus [24]. Quantification of levels of both markers of oxidative stress, and endogenous antioxidant proteins such as superoxide dismutase (SOD), and glutathione peroxidase revealed an immediate increase within a few hours of insult, with return to normal levels by 5 days. After whole body blast in rats, the increase in these markers of oxidative stress was greater when compared to local blast rats, except for glutathione peroxidase [24]. The levels were also elevated in direct proportion to injury severity.

Another line of evidence for neuronal consequences of blast is the presence of immediate early genes previously demonstrated to be associated with neuronal damage. Phosphorylated c-Jun is recognized as a marker of neuronal stress, and appears to be a signal for induction of apoptosis. In rodents exposed to impulse noise (a pressure pulse wave approximating that seen when handling heavy weap- ons), Säljö et al noted immunopositivity for c-Jun in the temporal, cingulate and piriform cortices, as well as CA 1, 2, 3 and dentate gyrus of the hippocampus. Ter- minal dUTP nick-end labeling (TUNEL) for double stranded DNA nicks co-localized with c-Jun staining, and supports the production of neuronal death in ' 2 – 5 % of neurons surveyed in this model, with a relatively modest injury level [29]. The early gene, c-Myc, has been implicated in the activation of caspases, mediators of apoptosis. In this model, neuronal and astrocytic c-Myc immunoreactivity in rats peaked at 18 h after injury in identical regions to c-Jun, as did c-Fos [30]. This suggests a timeline for neuronal death, and possible opportunities for aborting these pathways.

Unregulated calcium influx in injured neurons results in cellular dysfunction and is associated with energy failure. To this end, Cernak et al. compared magnesium, calcium, ATP, and water levels in the lungs and brainstem of rabbits exposed to local pulmonary blast injury only [31]. Immediately following injury, in lung tissue, there were markedly increased amounts of water and calcium, and decreased levels of magnesium and ATP. In the brainstem, the findings were similar, with increased brain water and decreased magnesium and ATP. Calcium levels increased in the brainstem, but not to a significant degree. These findings suggest that blast TBI has many features of other forms of TBI: Edema, calcium cytotoxicity, energy depletion.

This study also supports the notion that indirect blast induces brain injury; perhaps through acceleration-deceleration, transmission of blast overpressure out of the thorax, ischemia, or hypoxia from apnea, lung injury or hemorrhagic shock, or extreme excitation of brain tissue from afferent nerve impulses from damaged tissues [24].

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Role of Secondary Injury

Critically wounded blast victims pose a distinct therapeutic challenge in expeditious prevention of secondary insults and mitigation of harmful physiologic responses.

Despite recognition of the blast-related TBI spectrum, the responsible mechanisms (primary blast overpressure vs secondary and tertiary injuries) are extremely diffi- cult to separate in a real-time patient encounter. However, what is paramount is the substantial risk of secondary insults in this milieu of life-threatening multiple trauma.

Previous publications in civilian TBI have unequivocally established that TBI outcomes are often dismal when hypotension occurs [32]. This relationship is also seen in the setting of blast injury. In a recent combat casualty review of close proximity blast, the single most important predictor of mortality was the presence of hypotension; and when any combination of penetrating head injury, multiple long bone fractures or associated incident fatalities were present, mortality was 86 % [33].

Hemorrhagic hypotension from internal bleeding, fracture, traumatic amputation and multiple shrapnel wounds is an important cause of secondary insult: 1) there are often prolonged extraction times in the field, 2) injuries cannot always be defini- tively managed in the field, 3) adequate volumes of resuscitative fluids may not be available, and 4) administration of crystalloids in the face of ongoing blood loss can result in accelerated hemorrhage and hemodilution with impaired oxygen delivery and coagulation. Reduced cerebral blood flow (CBF) in the face of enhanced metabolic demands is due to TBI related loss of cerebrovascular autoregulation, and inadequate circulating blood volume and perfusion pressure. There is also evidence that TBI blunts an appropriate blood pressure response to volume resuscitation in hypovolemic shock. Additionally, there is experimental evidence that blast overpressure causes immediate bradycardia, hypotension and reduced cardiac index. Irwin et al were able to prevent bradycardia and hypotension in experimental blast injury with bilateral cervical vagotomies and administration of atropine, suggesting maladaptive physiologic responses related to vagal reflexes [34]. Several studies have demonstrated electroencephalogram (EEG) slowing and attenuation after exposure to blast, and the reproducibility of brainstem and white matter pathology also cor- roborates the occurrence of centrally mediated processes.

Second only to hypotension, hypoxemia is a significant factor predicting poor outcome in TBI patients [32]. Clark et al. demonstrated increased hippocampal neuronal death and decreased early motor function performance in rodents subjected to experimental TBI and secondary hypoxic insult [35]. Apnea, hypoventilation, and impaired gas exchange from brainstem and lung pathology are certainly implicated in this paradigm. Ischemia from hemorrhagic shock also contributes relative tissue hypoxia in a failure of oxygen and substrate delivery.

Free radical production, inflammation, and excitotoxicity occur as direct consequences of TBI, but there is also speculation that extra-cerebral and endothelial injuries elaborate harmful products into the circulation that exacerbate TBI upon reaching the cerebral vasculature and brain tissue. One such hypothesis is that as blast overpressure traverses the body, rupture of blood vessels leads to hemorrhage and endothelial activation. Red blood cells are also disrupted, releasing hemoglobin that is oxidized, catalyzing free radical formation. The ensuing oxidative stress per- petuates cellular injury [36]. In addition, hemoglobin has the ability to bind NO, thereby possibly contributing to ischemia and impaired oxygenation by vasoconstriction in the microcirculation. Further actions of free radicals in the brain con-

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tribute to increased blood brain barrier (BBB) permeability and ultimately cerebral edema, as well as enhanced inflammatory cell responses. Extracerebral effects of blast-injury and shock on systemic elaboration of cytokines, endotoxin, and/or other potentially toxic mediators of secondary damage in brain are also possible – but remain to be explored and fully characterized.

The challenge of preventing and/or promptly and optimally treating secondary insults in critically wounded severe TBI patients is a pressing military and civilian concern. Not only could advances in far-forward and pre-hospital resuscitation strategies reduce mortality; novel therapies and resuscitation fluids could significantly impact the morbidity of TBI, resulting in a greater percentage of ‘good’ or

‘excellent’ neurologic outcomes.

Future Directions in Therapeutic Interventions

Amidst the reality of civilian mass casualty and hostile battlefield environments, where chaos and limited available resources are commonplace, optimal evacuation, triage and resuscitation of TBI and combined systemic trauma is not always feasible.

Effective, practical interventions to both prevent secondary insults and mitigate maladaptive physiologic responses would, therefore, represent a significant break- through. Furthermore, if blast-related TBI exhibits unique pathobiology, prehospital and neurointensive care interventions specific to the constellation of physiology and molecular alterations would be invaluable.

Expedient initial treatment of hypotension and prevention of additional hypoten- sive episodes can be achieved with volume resuscitation and control of hemorrhage sites. Resuscitation fluid may not be readily available, however; for example, a battlefield medic can only carry a finite amount of equipment. Furthermore, the use of crystalloids for volume expansion is only temporizing, as critically wounded patients rapidly require blood products to restore homeostasis. Far-forward providers should be equipped with necessary supplies for abating hemorrhage, and provision of recombinant activated factor VII should be considered for life-threatening bleeding [37, 38].

Fresh whole blood is now being used early in the resuscitation phase by the US Army in the setting of major hemorrhage in the Iraq War (Holcomb, presented at ATACCC, St. Pete Beach, FL, August 2006). A novel resuscitation fluid to expand blood volume in smaller aliquots than conventional fluids would be ideal. If this compact fluid could also provide oxygen delivery, osmotic or oncotic pressure, or other mediators of immediate injury, it would be significant. Hypertonic saline restores blood pressure in much smaller amounts than isotonic fluids as interstitial fluid moves into the intravascular compartment to equilibrate the osmotic gradient.

In addition, hypertonic saline avoids hyposmolarity and is effective in treatment of increased ICP [39]. However, its efficacy in this specific setting remains to be defini- tively proven. Currently Hextend is the standard resuscitation fluid of the US military [40]. Mannitol has long been used as a hyperosmolar therapy for increased ICP, and does cause an immediate rise in blood pressure and drop in ICP; however, this is followed by osmotic diuresis, which is not desirable in patients with hypovolemic shock. Hypertonic saline increases cerebral perfusion by expanding circulating blood volume while at the same time ameliorating intracranial hypertension. Thus, there may be theoretical advantages for its use. There remains concern regarding BBB permeability in injured brain, permitting hypertonic fluid leakage into tissue

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and contributing to vasogenic edema. It follows then, that a strategy to maintain BBB integrity would be a desirable adjunct. Immediate BBB breach and tissue damage from the inciting injury cannot be prevented, but further compromise from hypotension, hypoxemia, inflammation, oxidative stress and endothelial activation are reasonable therapeutic targets for future therapies.

Vasogenic edema is only one mechanism of brain swelling. Cytotoxic edema also ensues. To this end, a family of membrane water channel proteins known as aquapo- rins serve to regulate fluid shifts into and out of neurons and astrocytes. Aquaporin knockout mice exhibit reduced edema and decreased ICP and brain water content after experimental TBI [41]. Manipulation of these transmembrane proteins might be an effective therapeutic option in the amelioration of evolving edema and increased ICP.

Disturbed cerebral blood flow (CBF) is another priority for further study and intervention. Cerebrovascular autoregulation is lost after injury, and in the face of low or high blood pressure extremes, this can be catastrophic. Thrombosis and platelet aggregation, direct vascular disruption, and tissue swelling contribute to impaired blood flow [42]. Vasospasm may be of special importance in blast induced TBI related to the extremely high prevalence of subarachnoid hemorrhage in experimental models of this condition. Whether or not triple H therapy – as used in the treatment of vasospasm after subarachnoid hemorrhage – is beneficial in blast- induced TBI remains to be determined [43]. Vascular perturbations such as reduced endogenous NO or other vasodilators, and increased factors such as endothelin-1 contribute to vasoconstriction [44]. On the other hand, vasodilation and markedly elevated cerebral blood volume can contribute to increased ICP. In the field, it is impossible to discern what the cerebrovascular milieu is; however, judicious applica- tion of diagnostic modalities upon arrival to definitive care, such as tissue oxygen monitoring and bedside cranial Doppler ultrasound, might guide optimal blood pressure range or use of vasoactive drugs by providing insight into the presence and nature of vascular dysfunction.

Formation of free radicals (reactive oxygen and nitrogen species) in TBI and systemic trauma as well as experimental blast injury elaborate secondary injury via membrane lipid peroxidation, altered protein conformation and binding, inflammation, endothelial activation and microcirculatory disarray. Antioxidant strategies and inhibitors of lipid peroxidation have the potential to dramatically impact this aspect in both isolated TBI and TBI in the context of severe polytrauma.

Blood substitute formulation has been attempted, but is as yet unsuccessful.

Albumin is an attractive colloid molecule for inclusion in such a fluid, however, the albumin molecule can induce oxidative stress when associated metal moieties become redox active in vivo. This may explain the increased mortality of critically ill patients in several albumin studies, one of which demonstrated an increased mortality in the subset of TBI patients, although other mechanisms may be involved [45].

The addition of hemoglobin for augmented oxygen delivery in addition to oncotic pressure is promising as well. However, previous formulations have been fraught with multi-organ system failure complications, likely due to the oxidative stress induced by free hemoglobin. Novel formulations that mitigate these adverse effects would be advantageous in the setting of limited or unavailable blood products.

Initially, it appears that electrical brain activity is attenuated after blast. As brain injury evolves, subsequent excitotoxicity exacerbates neuronal damage. Anti-epilep- tic medications, barbiturates, anesthetic agents, and hypothermia mitigate this response. Other possible therapies include hypothermia and compounds to block N-

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methyl-D-aspartate (NMDA) receptors and inhibit accumulation of glutamate, gly- cine, excitotoxic amino acids, and calcium early after injury. As calcium accumulates in neurons, mitochondrial damage ensues, resulting in energy failure and cell death via necrosis or apoptosis. Cyclosporine-A has been shown to abate the formation of a membrane permeability transition pore, thereby protecting mitochondria and conferring neuroprotection in experimental models [46]. While necrosis occurs due to essential failure of the cell, apoptosis is more complex, requiring initiators and signal cascades. Drugs to block the various steps in this process while homeostasis is disturbed may prevent neuronal death, or at least increase the likelihood that the cell will survive long enough for favorable conditions to return.

Therapeutic hypothermia is neuroprotective in experimental models of ischemia, hypoxemia, cardiac arrest, hemorrhagic shock, and TBI [47]. Hypothermia attenuates excitotoxicity, free radical production and inflammation, reduces metabolic expenditure, and decreases ICP. Results of mild therapeutic hypothermia on survival and neurologic outcome after cardiac arrest have been favorable, while clinical trials of therapeutic hypothermia for TBI patients have failed to demonstrate consistent neuroprotection. However, it is important to recognize that patients with clinically significant hypotension were excluded from TBI trials. Hemorrhagic shock from blast injuries add an ischemic insult to TBI, thus the combination of TBI with associated orthopedic and internal injuries typical of blast mechanisms would seem amenable to treatment with mild hypothermia [48]. Inability to control hemorrhage in this setting, suggests the potential need to combine mild cooling with therapies supplementing coagulation. This combined approach merits future investigation.

When inter- and intra-cellular aberrancies are considered simultaneously, it is abundantly clear that the most effective therapeutic approach will be multipronged and incorporate many different modalities. In addition, advances in genetic testing may allow the identification of persons with susceptible genetic polymorphisms, facilitating individual treatment plans. It is exceedingly unlikely that a single ‘magic bullet’ will emerge. Rather, the best intervention for each target in injury progres- sion will need to be gauged by pre-hospital and neurointensive care providers. It remains to be seen what variety of therapeutic options will become available.

Finally, current treatment of blast-induced TBI in the military setting involves the use of decompressive craniectomy [2]. This may be an important strategy for con- trolling raised ICP in this setting. Additional experimental and clinical studies are needed.

Conclusion

Explosive munitions were once an inevitable aspect of armed military action, broach- ing civilian consciousness only in the context of war. Innocent inhabitants caught up in regional conflict, or victims of abandoned mine fields comprised the civilian por- tion of blast injuries not related to industrial accidents. Sadly, improvised explosive devices and civilian bombings have become a key aspect of the urban battlefield and politically motivated terrorism incidents. Military and civilian providers alike have been forced to re-examine their approach to victims as more patients are surviving to hospital admission than in previous experiences due to advances in prehospital care. Despite being a relatively crude weapon, improvised explosive devices have evolved a frightening level of sophistication and the indiscriminate and unpredictable nature of this modality is the essence of its effectiveness.

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In response to this distinct pattern of injury, the medical research community and care providers are applying previously accumulated knowledge and techniques and moving in new directions to elucidate the precise nature of blast-related injuries, so that ideal therapies may be developed and employed. Ironically, blast-related TBI is similar to previous patterns of TBI such as DAI, traumatic subarachnoid hemorrhage and TBI exacerbation by hemorrhagic shock, aspects that have previously been investigated, but deserve additional study. It is likely that in the face of this new challenge, many questions that have yet to be fully answered will still need to be addressed. Bench research findings should be integrated with bedside observations, and novel therapies and intelligent resuscitation strategies will need to be developed in the context of the complexity of TBI.

Acknowledgement: We thank the United States Army PR054755 (PK), and the National Institutes of Health, USA, NS 38087 (PK) and NS 30318 (PK) for support.

References

1. Cernak I, Savic J, Ignjatovic D, Jevtic M (1999) Blast injury from explosive munitions. J Trauma 47:96 – 104

2. Okie S (2005) Traumatic brain injury in the war zone. N Engl J Med 352:2043 – 2047 3. Zouris JM, Walker GJ, Dye J, Galarneau M (2006) Wounding patterns for US marines and

sailors during operation Iraqi freedom, Major Combat Phase. Mil Med 171:246 – 252 4. Gondusky JS, Reiter MP (2005) Protecting military convoys in Iraq. Mil Med 170:546 – 549 5. Kluger Y, Peleg K, Daniel-Aharonson L, The Israeli Trauma Group (2004) The special injury

pattern in terrorist bombings. J Am Coll Surg 199:875 – 879

6. Peleg K, Aharonson-Daniel L, Stein M, et al (2004) Gunshot and explosion injuries. Ann Surg 239:311 – 318

7. Hadden WA, Rutherford WH, Merrett JD (1978) The injuries of terrorist bombing: a study of 1532 consecutive patients. Br J Surg 65:525 – 531

8. Born CT (2005) Blast trauma: The fourth weapon of mass destruction. Scan J Surg 94:

279 – 285

9. Mayorga MA (1997) The pathology of primary blast overpressure injury. Toxicology 121:

17 – 28

10. Elsayed NM (1997) Toxicology of blast overpressure. Toxicology 121:1 – 15 11. Phillips YY (1986) Primary blast injuries. Ann Emerg Med 15:1446 – 1450

12. Phillips YY, Richmond DR (1991) Primary blast injury and basic reasearch. In: Textbook of Military Medicine, part 1, vol 1, Office of the Surgeon General, US Army, pp 221 – 240 13. Stuhmiller JH, Phillips YY, Richmond DR (1991) The physics and mechanics of primary blast

injury. In: Textbook of Military Medicine, part 1, vol 1, Office of the Surgeon General, US Army, pp 241 – 270

14. Sharpnack DD, Johnson AJ, Phillips YY (1991) The pathology of primary blast injury. In:

Textbook of Military Medicine, part 1, vol 1, Office of the Surgeon General, US Army, pp 271 – 294

15. Guy RJ, Cripps NPJ (2000) Primary blast injury. J R Nav Med Serv 86:27 – 31

16. Mott FW (1916) The effects of high explosives upon the central nervous system. Lancet 1:331 – 338

17. Mott FW (1917) The microscopic examination of the brains of two men dead of commotio cerebri (shell shock) without visible external injury. J R Army Med Corps 29:662 – 677 18. Knudsen SK, Øen EO (2003) Blast-induced neurotrauma in whales. Neurosci Res 46:377 – 386 19. Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982) Dif-

fuse axonal injury and traumatic coma in the primate. Ann Neurol 12:564 – 574

20. Wood H, Sweetser HB (1940) Punctate cerebral hemorrhage following thoracic Trauma. Nav Med Bull 46:51 – 56

21. Levi L, Borovich B, Guilburd J, et al (1990) Wartime neurosurgical experience in Lebanon, 1982 – 85 II. Israel J Med Sci 26:555 – 578

(11)

22. Yuan XQ, Wade CE (1992) Traumatic brain injury attenuates the effectiveness of lactated ringer’s solution resuscitation of hemorrhaginc shock in Rats. Surg Gynecol Obstet 174:305 – 312

23. Chesnut RM, Gautille T, Blunt BA, Klauber MR, Marshall LF (1998) Neurogenic hypotension in patients with severe head injuries. J Trauma 44:958 – 963

24. Cernak I, Wang Z, Jiang J, Bian X, Savic J (2001) Ultrastructural and functional characteris- tics of blast injury-induced neurotrauma. J Trauma 50:695 – 706

25. Säljö A, Bao F, Haglid KG, Hansson H (2000) Blast exposure causes redistribution of phosphorylated neurofilament subunits in neurons of the adult rat brain. J Neurotrauma 17:

719 – 726

26. Kaur C, Singh J, Lim MK, Ng BL, Yap EPH, Ling EA (1996) Studies of the choroid plexus and its associated epiplexus cells in the lateral ventricles of rats following an exposure to a single non-penetrative blast. Arch Histol Cytol 59:239 – 248

27. Kaur C, Singh J, Lim MK, Ng BL, Yap EPH, Ling EA (1995) The response of neurons and microglia to blast injury in the rat brain. Neuropath App Neurobio 21:369 – 377

28. Bayir H, Kagan VE, Tyurina YY, Tyurin V, Ruppel R, Adelson PD (2002) Assessment of antioxidant reserves and oxidative stress in CSF after severe TBI in infants and children. Ped Res 51:571 – 578

29. Saljo A, Bao F, Jingshan S, Hamberger A, Hansson H, Haglid KG (2002) Exposure to short- lasting impulse noise causes c-Jun expression and induction of apoptosis in the adult rat brain. J Neurotrauma 19:985 – 991

30. Saljo A, Bao F, Shi J, Hamberger A, Hansson H, Haglid K (2002) Expression of c-Fos and c- Myc and deposition of B-APP in neurons in the adult rat brain as a result of exposure to short-lasting impulse noise. J Neurotrauma 19:379 – 385

31. Cernak I, Radosevic P, Malicevic Z, Savic J (1995) Experimental magnesium depletion in adult rabbits caused by blast overpressure. Mag Res 8:249 – 259

32. Chesnut RM, Marshall SB, Piek J, Blunt BA, Klauber MR, Marshall LF (1993) Early and late systemic hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in the traumatic coma data bank. Acta Neurochir Suppl 59:121 – 125 33. Nelson TJ, Wall DB, Stedje-Larsen ET, Clark RT, Chamber LW, Bohman HR (2006) Predictors

of mortality in close proximity blast injuries during operation iraqi freedom. J Am Coll Surg 202:418 – 422

34. Irwin RJ, Lerner MR, Bealer JF, Mantor C, Brackett DJ, Tuggle DW (1999) Shock after blast wave injury is caused by a vagally mediated reflex. J Trauma 47:105 – 110

35. Clark RSB, Kochanek PM, Dixon CE, et al (1997) Early neuropathologic effects of mild or mod- erate hypoxemia after controlled cortical impact injury in rats. J Neurotrauma 14:179 – 189 36. Elsayed NM, Gorbunov NV, Kagan VE (1997) A Proposed biochemical mechanism involving

hemoglobin for blast overpressure-induced injury. Toxicology 121:81 – 90

37. Gowers CJ, Parr MJ (2005) Recombinant activated factor VIIa use in massive transfusion and coagulopathy unresponsive to conventional therapy. Anaesth Intensive Care 33:196 – 200 38. Holcomb JB, Hoots K, Moore FA (2005) Treatment of an acquired coagulopathy with recom-

binant activated factor VII in a damage-control patient. Mil Med 170:287 – 290

39. Bhardwaj A, Ulatowski JA (2004) Hypertonic saline solutions in brain injury. Curr Opin Crit Care 10:126 – 131

40. Holcomb JB (2003) Fluid resuscitation in modern combat casualty care: Lessons learned from Somalia. J Trauma 54:S46-S51

41. Manley GT, Binder DK, Papadopoulos MC, Verkman AS (2004) New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience 129:983 – 991

42. Dietrich WD, Alonso O, Busto R, et al (1996) Widespread hemodynamic depression and focal platelet accumulation after fluid percussion brain injury. J Cereb Blood Flow Metab 16:481 – 489 43. Lee KH, Lukovits T, Friedman JA (2006) “Triple-H” therapy for cerebral vasospasm following

subarachnoid hemorrhage. Neurocrit Care 4:68 – 76

44. Andresen J, Shafi NI, Bryan RM (2005) Endothelial influences on cerebrovascular tone. J Appl Physiol 100:318 – 327

45. The SAFE Study Investigators (2004) A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247 – 2256

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46. Scheff SW, Sullivan PG (1999) Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma 16:783 – 792 47. Kochanek PM, Jenkins LW, Clark RSB (2005) Traumatic brain injury: laboratory studies. In:

Tisherman SA, Sterz F (eds) Therapeutic Hypothermia, Springer Science + Business Media, Inc., New York, pp 63 – 86

48. Wu X, Kochanek PM, Cochran K, et al (2005) Mild hypothermia improves survival after prolonged, traumatic hemorrhagic shock in pigs. J Trauma 59:291 – 299